Atherosclerosis is the accumulation of lipid-fibrin plaques on the luminal wall of vascular endothelial cells. The presence of atherosclerotic plaques can severely diminish vascular flow to target organs, leading to morbidity and mortality. Atherosclerotic plaques may occur in coronary arteries (coronary artery disease, “CAD”, which can cause angina and heart attacks), in carotid arteries (carotid artery disease, which can cause stroke), and in arteries of the limb (usually affecting the leg arteries, also known as peripheral artery disease, “PAD”). Individuals may have narrowings in one or more of these regions. There are approximately 15 million individuals in the US with CAD; 8 million people with PAD; and about 5 million people with carotid artery disease. Whereas carotid and coronary artery disease are usually recognized by physicians, the diagnosis of PAD is usually missed.
The PARTNERS trial was a recent screening study which examined the prevalence of PAD in smokers or diabetics over the age of 55, or any individual over the age of 70, which were visiting their primary practitioner for a routine visit (Hirsch AT et al., “Peripheral arterial disease detection, awareness, and treatment in primary care,” JAMA, 286: 1317-24 (2001)). In over 7000 patients that were screened, over 25% were found to have PAD, as detected by an ankle pressure measurements. Unfortunately, only ⅓ of these patients had previously been diagnosed. The majority had been unrecognized by their doctors as having PAD. PAD is commonly under-diagnosed and under-treated in part because many patients do not manifest the classic symptomatology. Exertional leg pain relieved by rest is only noted by 10-30% of patients (Hirsch et al., above). As a consequence, appropriate treatment for atherosclerosis is not initiated in many of these patients.
Because PAD patients are underdiagnosed and undertreated, they are at higher risk for cardiovascular death. Untreated PAD can lead to decreased mobility, ulcers, gangrene, and may ultimately require amputation of the affected extremity. Patients with PAD are at increased risk from myocardial infarction, cerebrovascular attack, aortic aneurym rupture, and vascular death (Criqui M H et al, “The epidemiology of peripheral arterial disease: importance of identifying the population at risk,” Vasc Med., 2:221-6 (1997); Meijer W T et al., “Peripheral arterial disease in the elderly: The Rotterdam Study,” Arterioscler Thromb Vasc Biol., 18:185-92 (1998)).
A useful screening test for PAD is the ankle-brachial index (“ABI”). The ABI requires that the blood pressure be taken at the arm, and at the ankle. One calculates the ratio of the systolic pressure in the lower extremity to that in the upper extremity. In most healthy individuals, the ratio is close to 1 (i.e., 0.90 or greater) while in patients with a ratio less than 0.90, PAD is diagnosed. Generally, the lower the ratio, the more severe the disease. To assess the pressure at the ankle, one needs to use special equipment, i.e., a Doppler ultrasound probe. A simple stethoscope will not suffice because the leg vessels of adults tend to be stiffer than those in the arm, and do not generate Korotkoff sounds during deflation of the blood pressure cuff. Unfortunately, the Doppler ultrasound equipment requires special training, and is not used in the offices of primary practitioners. Accordingly, PAD is usually not diagnosed. Moreover, in patients with diabetes, who constitute over 30% of patients with PAD, poor vascular compressibility may cause the ABI test to yield false negatives.
PAD, when diagnosed early, is amenable to treatments which slow progression of the disease. Also, medications known to prevent heart attacks and strokes in patients with atherosclerosis (e.g., anti-platelet agents, statins, angiotensin converting enzyme inhibitors) are underutilized in PAD patients. Therefore, a need exists for screening tests which will alert the clinician to the possibility that their patient may have PAD. In particular, a blood test for PAD would be helpful since it could be performed in a routine clinical setting.